PROJECT 3 (HORAK): ABSTRACT Balance/gait disorders associated with genetic inheritance in PD Cognitive deficits and balance/gait (B&G) disorders are both progressive but heterogeneous among people with Parkinson's disease (PD), and may be due in part to genetic factors. The inaugural PANUC award demonstrated that APOE ?4 or GBA variants increases the risk for different types of cognitive impairment in PD. Project 3 will test the hypothesis that the pattern of B&G abnormalities, in part an expression of various types of cognitive impairment, differ in PD subjects with APOE ?4, GBA variants, or neither. B&G will be characterized in all Clinical Core participants using novel, inertial-sensors worn on the feet, belt, and wrist. A quick Instrumented Stand and Walk protocol that involves standing quietly for 30 seconds, followed by step- initiation, a 2-minute walk, and several 180 degree turns quantifies various domains of mobility disability, such as postural sway area, gait pace, and gait rhythm. The B&G protocol will also be repeated during simultaneous performance of a quantitative cognitive task to determine the effects of divided attention on B&G. We will test our hypotheses with three specific aims: 1) Cross-sectional: Determine patterns of B&G dysfunction in PD with APOE ?4, GBA variants, or neither, and relate B&G to cognitive impairments in these genetically-defined subsets of PD; 2) Physiological: Relate central cholinergic tone, measured with SAI, to impairments of B&G and attention in in genetically-defined subsets of PD; and 3) Longitudinal: Determine the longitudinal decline of B&G, attention, and cholinergic tone in genetically-defined subsets of PD. This work is significant because it will expand our knowledge of genetic risk for severity and decline in mobility as they relate to cognitive impairments in PD, and lay the foundation for potential cholinergic mechanisms linking cognitive with B&G dysfunction. Insights from this project, integrated within the PANUC, will provide new biomarkers for cognitive and mobility decline for better prognosis and interventions for patients with PD.